Normal human bronchial epithelial (NHBE) cells and lung carcinoma cell lines were used to investigate the effects of putative human tumor promoters. Compounds were selected on the basis of known tumor-promoting activity in experimental animals or epidemiological evidence that they play a role in human cancer. We have previously reported that the mouse epidermal tumor promoter 12-0-tetrade-canoylphorbol-13-acetate (TPA) induces terminal differentiation in NHBE cells; thus far, no resistant cells have grown from cultures of presumably normal, noninitiated bronchial epithelial cells after treatment with TPA. In contrast, all carcinoma cell lines are resistant to TPA-induced terminal differentiation. We have now investigated the effect of other putative tumor promoters on markers of terminal differentiation in NHBE cells. We find that aplysiatoxin, debromoaplysiatoxin, teleocidin, cigarette smoke condensate (CSC), and fractions thereof increase cross-linked envelope formation and plasminogen activator activity and decrease epidermal growth factor (EGF) binding after a 12 to 24 hour incubation. We selected four fractions of CSC for further investigations based on their capacity to serve as tumor promoters in the mouse skin model, including insoluble basic fractions alpha and beta (BIa, BIb), ethanol-extracted weakly acidic fraction (WAE), and methanol-extracted neutral fraction (Nmeoh). Of these, Nmeoh had the greatest capacity to inhibit growth, induce CLE and plasminogen activator, induce a squamous morphology, and decrease EGF binding.